Among α-substituted cysteines, optically active α-substituted cysteines are especially useful as intermediates for pharmaceuticals. Various methods are conventionally known as methods for producing α-substituted cysteines and salts thereof (for example, Patent Document 1).
However, the conventional methods have been impractical since stable production in an industrial scale has been difficult because of, for example, requirement of a low-temperature reaction using an expensive base such as butyllithium, and/or requirement of many laborious steps using a large amount of expensive reagents.
As a method that does not require an expensive reagent or a low-temperature reaction unlike the method in Patent Document 1, Patent Document 2 describes a method for producing α-methyl-D-cysteine in which racemic N-carbamoyl-α-methylcysteine is subjected to D-isomer-specific cyclization by hydantoinase to produce D-5-methyl-5-thiomethylhydantoin, followed by hydrolysis, decarbamoylation, and sulfur atom deprotection (elimination of the tert-butyl group) of the D-5-methyl-5-thiomethylhydantoin. This α-methyl-D-cysteine is an optically active α-substituted cysteine, and useful as an intermediate for a therapeutic agent for hyperferremia.
Patent Document 3 describes a method for obtaining benzyl-protected α-methyl-D-cysteine by allowing Bacillus licheniformis protease to act on a diester having benzyl-protected thiol to provide an (S)-monoester, and then converting the isocyanate group generated by Curtius rearrangement to an amino group.
Non-patent Document 1 discloses a method for obtaining tert-butyl-protected α-methyl-D-cysteine, wherein a diester protected with a tert-butyl group instead of a benzyl group is subjected to (R)-monoesterification using pig liver esterase, and then to tert-butyl esterification of the carboxyl group and hydrolysis of the methyl ester to obtain an (S)-monoester, followed by converting the isocyanate group generated by Curtius rearrangement to a carbamate-protected amino group, and then deprotecting the carbamate protection.
Non-patent Document 2 describes a production method in which the tert-butyl-protected diester described in Non-patent Document 1, tert-butylthiochloromethane, and methyl dialkylmalonate are reacted in the presence of a base. The document also describes a method for producing tert-butylthiochloromethane, in which tert-butyl mercaptan, paraformaldehyde, and hydrogen chloride are reacted in dichloromethane. It is known that, in this process, contacting of formaldehyde with hydrogen chloride causes generation of bis-chloromethylether (for example, Non-patent Document 3).